PROJECT SUMMARY The potential hazardous effects of inhalation exposure to semi-volatile PCBs in ambient and indoor environ- ments have caused growing concern and demonstrated the need for research in inhalation toxicology of airborne PCBs. The paucity of data on metabolism, excretion, and dose-specific toxicologic effects has been the main barrier to meaningful human health risk assessment of inhaled PCBs, especially of the non-legacy, semi-volatile PCBs. In this grant cycle, the former Inhalation Toxicology Core is elevated to project status in recognition of the formative and highly innovative research this group has performed. Project 7 is highly integrated with other projects and cores of the Iowa Superfund Research Program (isrp) and will continue to provide tissues, blood and excreta from inhalation-exposed animals and controls. As a project, this research team will expand the body of knowledge on inhaled PCBs using innovative exposure systems and methodol- ogy developed in the last cycle. We will conduct studies to identify adverse outcome pathways (AOPs) for inhaled environmentally-relevant PCB mixtures and identify both the no observed adverse effect level (NOAEL) and the lowest observed adverse effect level (LOAEL). We will test multiple dose levels using a congener profile that we have demonstrated represents the Chicago airshed. The study will, for the first time, reduce uncertainties in the inhalation reference concentration (RfC) for risk assessment and present an extensive dose-dependent evaluation of AOPs. Adverse outcomes measured in adult rats and mice will be further investigated in prenatal exposure studies, recognizing the enhanced susceptibility of pregnancy and the developing fetus. In addition, collaboration with other projects of the isrp will provide mechanistic insights on how molecular and cellular processes respond in those pathways. Over the past 5 years, our publications have begun to fill what was a near total void on the biological fate of inhaled PCBs. We will continue to elucidate the absorption, distribution, metabolism and excretion (ADME) of predominant airborne PCBs using 14C-labelled congeners. Our central hypothesis is that even though inhaled environmental PCBs are susceptible to relatively fast elimination, inhalation exposure to rodents at current human equivalent concentrations will result in adverse health effects and measureable toxicity. Three specific aims will be addressed: AIM 1) Conduct inhalation studies using our Chicago Air Mixture (CAM+) to identify adverse outcome pathways and derive in vivo data for an integrated risk assessment; AIM 2) Conduct ADME toxicology studies with lung exposure to radiolabelled tetra- and penta- chlorobiphenyls to provide data for toxicokinetic modeling; and AIM 3) Investigate developmental, immune and neurologic toxicity after prenatal inhalation exposure to airborne PCBs (CAM+) at the LOAEL. The research proposed herein will significantly advance the understanding of the dose-specific toxicity of inhaled PCB mixtures and the operative AOPs and thus will facilitate the establishment of an integrated risk assessment for inhalation exposure to environmental PCBs.